Project summary/Abstract Peripheral nerve injuries are common with more than 200,000 new cases reported each year in the United States alone. Only about 10% of these individuals regain much function. Nerve injuries significantly impact the long-term quality of life, and many injured individuals seek continued life-long treatments for associated disabilities and pain. The common reason given for the poor functional outcomes is the process of axon regeneration. Over the past decade, our laboratory has shown that exercise strikingly enhances peripheral axon regeneration and significantly improves functional recovery following complete nerve. However, the translational potential of exercise has limitations. Many patients are not candidates for exercise due to issues, such as co-morbidities that preclude rehabilitation, necessary immobilization of a limb following surgical nerve repair, unknown dose requirement of exercise and patient compliance. We propose here a novel therapy for peripheral nerve injury that exploits a downstream effector of exercise (hypoxia inducible factor 1, HIF1) to promote sensory and motor axon regeneration in a non-invasive manner, and in a way that could be utilized by all nerve injury patients. Based on the literature, we suggest that HIF1? may be the key mediator of how exercise robustly promotes axon regeneration after nerve injury. The HIF complex controls the transcription of numerous genes associated with neurogenesis, neuronal survival, neuronal metabolism, and angiogenesis. De-regulation of HIF1? has been identified in several neurodegenerative diseases (e.g., amyotrophic lateral sclerosis) and neural injuries (e.g., spinal cord injury and stroke). Notably, neuronal HIF1? was shown to be required for axon regeneration after peripheral nerve injury. With pilot data, we show that the exercise protocol we have shown to enhance axon regeneration after sciatic nerve injury upregulates HIF1? in axotomized motoneurons. We also show that by pharmacologically stabilizing HIF1?, axons elongated even farther than after treatment with exercise. The goal of this study will be to investigate the fundamentals of pharmacologically stabilizing HIF1? in axotomized motor and sensory neurons to treat peripheral nerve injuries in males and females. Our proposed pharmacologic approach has been safely used long-term in humans, so that this approach would be practical to translate to human studies.